I cover cardiology news for CardioExchange, a social media website for cardiologists published by the New England Journal of Medicine. I was the editor of TheHeart.Org from its inception in 1999 until December 2008. Following the purchase of TheHeart.Org by WebMD in 2005, I became the editorial director of WebMD professional news, encompassing TheHeart.Org and Medscape Medical News. Prior to joining TheHeart.Org, I was a freelance medical journalist and wrote for a wide variety of medical and computer publications. In 1994-1995 I was a Knight Science Journalism Fellow at MIT. I have a PhD in English from SUNY Buffalo, and I drove a taxicab in New York City before embarking on a career in medical journalism. You can follow me on Twitter at: @cardiobrief.

FDA reviewers have raised serious questions about the results of the CHAMPION trial of the implantable CardioMEMS HF Pressure Measurement System (HF System), which provides daily pulmonary artery pressure measurements for the purpose of guiding heart failure treatment. On December 8 the FDA’s Circulatory System Devices Panel is scheduled to review the PMA for the device. (Click here for the FDA documents.)

The main FDA review concludes that the trial “met the primary effectiveness endpoint and both primary safety endpoints in the population studied, based upon their pre-specified hypotheses.” But, the review continues, “although statistically significant, FDA has questions about the clinical significance of the findings, in particular related to the primary effectiveness and several of the secondary effectiveness endpoints (Proportion of subjects hospitalized for heart failure, Days Alive Outside of the Hospital and Quality of Life).” The FDA said it “would like panel input on the overall risk/benefit profile and approvability of the device.”

An addendum to the main FDA review raises additional new concerns about the trial. An earlier report about these concerns was refuted by the company’s CEO and founder, cardiologist Jay Yadav, but with the release of the FDA documents it now appears that the earlier rumors were at least partially correct, though there is no evidence to show that CardioMEMS had knowledge of the new FDA concerns at the time.

The addendum to the FDA review discusses “information not present in the PMA submission… based on inspections conducted by” FDA monitors. The FDA reviewers write that the trial may have been biased because the company and the national principal investigators provided additional medical support to patients in the treatment group but not to control patients. It should be noted that the purpose of the single-blind design of the trial was to test whether information received from the device could improve HF treatment. The crux of the difference between the FDA and CardioMEMS therefore appears to be whether the company’s efforts to enforce protocol-mandated treatments fall outside the standard practice of a clinical trial.

Here is the text of the additional question the FDA will ask the panel on Thursday:

Additional Question

FDA is concerned that the conduct of the clinical trial may have biased the study results. Inspections coordinated by FDA’s Division of Bioresearch Monitoring (BIMO) identified evidence that the sponsor, who had knowledge of the randomization assignment, or the principal investigators routinely contacted investigational sites and made specific therapeutic recommendations for some Treatment Group study subjects, including

titration of medication doses,

addition or discontinuation of medications,

recommendations for outpatient intravenous medication administration,

the addition of medications that were not included in the protocol, and

sleep study evaluations not included in the protocol.

FDA is concerned that the study results may be biased by these recommendations because investigators did not receive similar treatment recommendations from the sponsor for Control Group study subjects. FDA’s interpretation of the protocol is that therapeutic changes were to be made by the study site investigators.

The information obtained through inspections coordinated by FDA’s Division of Bioresearch Monitoring raises concerns for FDA that specific therapeutic recommendations may have minimized heart failure hospitalizations for Treatment Group study subjects without an equivalent impact for Control Group study subjects. FDA is concerned that the study results may be biased and that the ability to interpret study results may be compromised by the trial conduct.

a. FDA is concerned that the specific treatment recommendations made by the sponsor may have introduced bias into the study results. Please discuss whether or not you agree with this concern.

b. If the specific treatment recommendations introduced bias into the study results, please discuss how this impacts the ability to interpret the study results.

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